The actin-binding protein EPS8 binds VE-cadherin and modulates YAP localization and signaling

J Cell Biol. 2015 Dec 21;211(6):1177-92. doi: 10.1083/jcb.201501089. Epub 2015 Dec 14.

Abstract

Vascular endothelial (VE)-cadherin transfers intracellular signals contributing to vascular hemostasis. Signaling through VE-cadherin requires association and activity of different intracellular partners. Yes-associated protein (YAP)/TAZ transcriptional cofactors are important regulators of cell growth and organ size. We show that EPS8, a signaling adapter regulating actin dynamics, is a novel partner of VE-cadherin and is able to modulate YAP activity. By biochemical and imaging approaches, we demonstrate that EPS8 associates with the VE-cadherin complex of remodeling junctions promoting YAP translocation to the nucleus and transcriptional activation. Conversely, in stabilized junctions, 14-3-3-YAP associates with the VE-cadherin complex, whereas Eps8 is excluded. Junctional association of YAP inhibits nuclear translocation and inactivates its transcriptional activity both in vitro and in vivo in Eps8-null mice. The absence of Eps8 also increases vascular permeability in vivo, but did not induce other major vascular defects. Collectively, we identified novel components of the adherens junction complex, and we introduce a novel molecular mechanism through which the VE-cadherin complex controls YAP transcriptional activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Antigens, CD / metabolism*
  • Binding Sites
  • Cadherins / metabolism*
  • Cell Cycle Proteins
  • Cell Line
  • Endothelium, Vascular / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphoproteins / metabolism*
  • Protein Binding
  • Protein Transport
  • Signal Transduction*
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, CD
  • Cadherins
  • Cell Cycle Proteins
  • Eps8 protein, mouse
  • Phosphoproteins
  • YAP-Signaling Proteins
  • Yap1 protein, mouse
  • cadherin 5